Effect of base–acid properties of the mixtures of water with methanol on the solution enthalpy of selected cyclic ethers in this mixture at 298.15 K

The enthalpies of solution of cyclic ethers: 1,4- dioxane, 12-crown-4 and 18-crown-6 in the mixture of water and methanol have been measured within the whole mole fraction range at T = 298.15 K. Based on the obtained data, the effect of base–acid properties of water– methanol mixtures on the solution enthalpy of cyclic ethers in these mixtures has been analyzed. The solution enthalpy of cyclic ethers depends on acid properties of water– methanol mixtures in the range of high and medium water contents in the mixture. Based on the analysis performed, it can be assumed that in the mixtures of high methanol contents, cyclic ethe

BPIFB1 (LPLUNC1) is upregulated in cystic fibrosis lung disease

Although the biology the PLUNC (recently renamed BPI fold, BPIF) family of secreted proteins is poorly understood, multiple array based studies have suggested that some are differentially expressed in lung diseases. We have examined the expression of BPIFB1 (LPLUNC1), the prototypic two-domain containing family member, in lungs from CF patients and in mouse models of CF lung disease. BPIFB1 was localized in CF lung samples along with BPIFA1, MUC5AC, CD68 and NE and directly compared to histologically normal lung tissues and that of bacterial pneumonia. We generated novel antibodies to mouse BPIF proteins to conduct similar studies on ENaC transgenic (ENaC-Tg) mice, a model for CF-like lung disease. Small airways in CF demonstrated marked epithelial staining of BPIFB1 in goblet cells but staining was absent from alveolar regions. BPIFA1 and BPIFB1 were not co-localised in the diseased lungs. In ENaC-Tg mice there was strong staining of both proteins in the airways and luminal contents. This was most marked for BPIFB1 and was noted within 2 weeks of birth. The two proteins were present in distinct cells within epithelium. BPIFB1 was readily detected in BAL from ENaC-Tg mice but was absent from wild-type mice. Alterations in the expression of BPIF proteins is associated with CF lung disease in humans and mice. It is unclear if this elevation of protein production, which results from phenotypic alteration of the cells within the diseased epithelium, plays a role in the pathogenesis of the disease

The characteristic blue spectra of accretion disks in quasars as uncovered in the infrared

Quasars are thought to be powered by supermassive black holes accreting surrounding gas. Central to this picture is a putative accretion disk which is believed to be the source of the majority of the radiative output. It is well known, however, that the most extensively studied disk model -- an optically thick disk which is heated locally by the dissipation of gravitational binding energy -- is apparently contradicted by observations in a few major respects. In particular, the model predicts a specific blue spectral shape asymptotically from the visible to the near-infrared, but this is not generally seen in the visible wavelength region where the disk spectrum is observable. A crucial difficulty was that, toward the infrared, the disk spectrum starts to be hidden under strong hot dust emission from much larger but hitherto unresolved scales, and thus has essentially been impossible to observe. Here we report observations of polarized light interior to the dust-emiting region that enable us to uncover this near-infrared disk spectrum in several quasars. The revealed spectra show that the near-infrared disk spectrum is indeed as blue as predicted. This indicates that, at least for the outer near-infrared-emitting radii, the standard picture of the locally heated disk is approximately correct. The model problems at shorter wavelengths should then be directed toward a better understanding of the inner parts of the revealed disk. The newly uncovered disk emission at large radii, with more future measurements, will also shed totally new light on the unanswered critical question of how and where the disk ends.Comment: published in Nature, 24 July 2008 issue. Supplementary Information can be found at http://www.mpifr-bonn.mpg.de/div/ir-interferometry/suppl_info.pdf Published version can be accessed from http://www.nature.com/nature/journal/v454/n7203/pdf/nature07114.pd

High platelet reactivity in patients with acute coronary syndromes undergoing percutaneous coronary intervention: Randomised controlled trial comparing prasugrel and clopidogrel

Background: Prasugrel is more effective than clopidogrel in reducing platelet aggregation in acute coronary syndromes. Data available on prasugrel reloading in clopidogrel treated patients with high residual platelet reactivity (HRPR) i.e. poor responders, is limited. Objectives: To determine the effects of prasugrel loading on platelet function in patients on clopidogrel and high platelet reactivity undergoing percutaneous coronary intervention for acute coronary syndrome (ACS). Patients: Patients with ACS on clopidogrel who were scheduled for PCI found to have a platelet reactivity ≥40 AUC with the Multiplate Analyzer, i.e. “poor responders” were randomised to prasugrel (60 mg loading and 10 mg maintenance dose) or clopidogrel (600 mg reloading and 150 mg maintenance dose). The primary outcome measure was proportion of patients with platelet reactivity <40 AUC 4 hours after loading with study medication, and also at one hour (secondary outcome). 44 patients were enrolled and the study was terminated early as clopidogrel use decreased sharply due to introduction of newer P2Y12 inhibitors. Results: At 4 hours after study medication 100% of patients treated with prasugrel compared to 91% of those treated with clopidogrel had platelet reactivity <40 AUC (p = 0.49), while at 1 hour the proportions were 95% and 64% respectively (p = 0.02). Mean platelet reactivity at 4 and 1 hours after study medication in prasugrel and clopidogrel groups respectively were 12 versus 22 (p = 0.005) and 19 versus 34 (p = 0.01) respectively. Conclusions: Routine platelet function testing identifies patients with high residual platelet reactivity (“poor responders”) on clopidogrel. A strategy of prasugrel rather than clopidogrel reloading results in earlier and more sustained suppression of platelet reactivity. Future trials need to identify if this translates into clinical benefit

Modelling of the regulation of the hilA promoter of type three secretion system of Salmonella enterica serovar Typhimurium

One of the most common modes of secretion of toxins in gram-negative bacteria is via the type three secretion system (TTSS), which enables the toxins to be specifically exported into the host cell. The hilA gene product is a key regulator of the expression of the TTSS located on the pathogenicity island (SPI-1) of Salmonella enterica serovar Typhimurium. It has been proposed earlier that the regulation of HilA expression is via a complex feedforward loop involving the transactivators HilD, HilC and RtsA. In this paper, we have constructed a mathematical model of regulation of hilA-promoter by all the three activators using two feedforward loops. We have modified the model to include additional complexities in regulation such as the proposed positive feedback and cross regulations of the three transactivators. Results of the various models indicate that the basic model involving two Type I coherent feedforward loops with an OR gate is sufficient to explain the published experimental observations. We also discuss two scenarios where the regulation can occur via monomers or heterodimers of the transactivators and propose experiments that can be performed to distinguish the two modes of regulator function

A randomized clinical trial of a peri-operative behavioral intervention to improve physical activity adherence and functional outcomes following total knee replacement

<p>Abstract</p> <p>Background</p> <p>Total knee replacement (TKR) is a common and effective surgical procedure to relieve advanced knee arthritis that persists despite comprehensive medical treatment. Although TKR has excellent technical outcomes, significant variation in patient-reported functional improvement post-TKR exists. Evidence suggests that consistent post-TKR exercise and physical activity is associated with functional gain, and that this relationship is influenced by emotional health. The increasing use of TKR in the aging US population makes it critical to find strategies that maximize functional outcomes.</p> <p>Methods/Design</p> <p>This randomized clinical trial (RCT) will test the efficacy of a theory-based telephone-delivered Patient Self-Management Support intervention that seeks to enhance adherence to independent exercise and activity among post- TKR patients. The intervention consists of 12 sessions, which begin prior to surgery and continue for approximately 9 weeks post-TKR. The intervention condition will be compared to a usual care control condition using a randomized design and a probabilistic sample of men and women. Assessments are conducted at baseline, eight weeks, and six- and twelve- months. The project is being conducted at a large healthcare system in Massachusetts. The study was designed to provide greater than 80% power for detecting a difference of 4 points in physical function (SF36/Physical Component Score) between conditions (standard deviation of 10) at six months with secondary outcomes collected at one year, assuming a loss to follow up rate of no more than 15%.</p> <p>Discussion</p> <p>As TKR use expands, it is important to develop methods to identify patients at risk for sub-optimal functional outcome and to effectively intervene with the goal of optimizing functional outcomes. If shown efficacious, this peri-TKR intervention has the potential to change the paradigm for successful post-TKR care. We hypothesize that Patient Self-Management Support to enhance adherence to independent activity and exercise will enhance uniform, optimal improvement in post-TKR function and patient autonomy, the ultimate goals of TKR.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00566826">NCT00566826</a></p

BLISS: an artificial language for learnability studies

To explore neurocognitive mechanisms underlying the human language faculty, cognitive scientists use artificial languages to control more precisely the language learning environment and to study selected aspects of natural languages. Artificial languages applied in cognitive studies are usually designed ad hoc, to only probe a specific hypothesis, and they include a miniature grammar and a very small vocabulary. The aim of the present study is the construction of an artificial language incorporating both syntax and semantics, BLISS. Of intermediate complexity, BLISS mimics natural languages by having a vocabulary, syntax, and some semantics, as defined by a degree of non-syntactic statistical dependence between words. We quantify, using information theoretical measures, dependencies between words in BLISS sentences as well as differences between the distinct models we introduce for semantics. While modeling English syntax in its basic version, BLISS can be easily varied in its internal parametric structure, thus allowing studies of the relative learnability of different parameter sets

Alcohol affects neuronal substrates of response inhibition but not of perceptual processing of stimuli signalling a stop response

Alcohol impairs inhibitory control, including the ability to terminate an initiated action. While there is increasing knowledge about neural mechanisms involved in response inhibition, the level at which alcohol impairs such mechanisms remains poorly understood. Thirty-nine healthy social drinkers received either 0.4g/kg or 0.8g/kg of alcohol, or placebo, and performed two variants of a Visual Stop-signal task during acquisition of functional magnetic resonance imaging (fMRI) data. The two task variants differed only in their instructions: in the classic variant (VSST), participants inhibited their response to a “Go-stimulus” when it was followed by a “Stop-stimulus”. In the control variant (VSST_C), participants responded to the “Go-stimulus” even if it was followed by a “Stop-stimulus”. Comparison of successful Stop-trials (Sstop)>Go, and unsuccessful Stop-trials (Ustop)>Sstop between the three beverage groups enabled the identification of alcohol effects on functional neural circuits supporting inhibitory behaviour and error processing. Alcohol impaired inhibitory control as measured by the Stop-signal reaction time, but did not affect other aspects of VSST performance, nor performance on the VSST_C. The low alcohol dose evoked changes in neural activity within prefrontal, temporal, occipital and motor cortices. The high alcohol dose evoked changes in activity in areas affected by the low dose but importantly induced changes in activity within subcortical centres including the globus pallidus and thalamus. Alcohol did not affect neural correlates of perceptual processing of infrequent cues, as revealed by conjunction analyses of VSST and VSST_C tasks. Alcohol ingestion compromises the inhibitory control of action by modulating cortical regions supporting attentional, sensorimotor and action-planning processes. At higher doses the impact of alcohol also extends to affect subcortical nodes of fronto-basal ganglia- thalamo-cortical motor circuits. In contrast, alcohol appears to have little impact on the early visual processing of infrequent perceptual cues. These observations clarify clinically-important effects of alcohol on behaviour

Does publication bias inflate the apparent efficacy of psychological treatment for major depressive disorder? A systematic review and meta-analysis of US national institutes of health-funded trials

Background The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. Methods and Findings We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972–2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges’ g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. Conclusion The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression

A novel malaria vaccine candidate antigen expressed in Tetrahymena thermophila

Development of effective malaria vaccines is hampered by the problem of producing correctly folded Plasmodium proteins for use as vaccine components. We have investigated the use of a novel ciliate expression system, Tetrahymena thermophila, as a P. falciparum vaccine antigen platform. A synthetic vaccine antigen composed of N-terminal and C-terminal regions of merozoite surface protein-1 (MSP-1) was expressed in Tetrahymena thermophila. The recombinant antigen was secreted into the culture medium and purified by monoclonal antibody (mAb) affinity chromatography. The vaccine was immunogenic in MF1 mice, eliciting high antibody titers against both N- and C-terminal components. Sera from immunized animals reacted strongly with P. falciparum parasites from three antigenically different strains by immunofluorescence assays, confirming that the antibodies produced are able to recognize parasite antigens in their native form. Epitope mapping of serum reactivity with a peptide library derived from all three MSP-1 Block 2 serotypes confirmed that the MSP-1 Block 2 hybrid component of the vaccine had effectively targeted all three serotypes of this polymorphic region of MSP-1. This study has successfully demonstrated the use of Tetrahymena thermophila as a recombinant protein expression platform for the production of malaria vaccine antigens